An Update on Clostridium difficile Infection: From

PowerPoint PresentationAn Update on Clostridium difficile Infection: From Infection Control to Treatment
1 Source: CDC Report "Antibiotic Resistance Threats in the United States, 2013” Lessa CF et al. NEJM 2015;372:825-34.
500,000 29,000
New 2011 Data
Lessa et al, N Eng J Med 2015: 34.2% of CDI cases were considered community-acquired
Kevin W. Garey, PharmD, MS. Professor and Chair University of Houston College of Pharmacy
Objectives
• Provide a state of the art update on C. difficile infection
• Focus on environmental contamination of C. difficile
• How do we treat this ubiquitous pathogen?
A History of C. difficile
1893 - pseudomembranous colitis first described
1935 - isolated in stool
antibiotic associated diarrhea
1996-2003 CDC reports rate of CDI increased from 31 cases per 100,000
persons to 61 cases per 100,000 persons
1. Heinlen L, Ballard JD. Clostridium difficile Infection. The American journal of the medical sciences. 2010;340(3):247-252. doi:10.1097/MAJ.0b013e3181e939d8. 2. The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move Valiente, E. et al. Clinical Microbiology and Infection , Volume 20 , Issue 5 , 396 - 404
2005 – US continues to report increased CDI
2008-11 – England directs significant
Current – continued persistence of RT
027 in North America and
decrease incidence in Europe
C. difficile is the main contributor to gastroenteritis-associated deaths in the USA
Analysis of National Center for Health Statistics (NCHS) multiple-cause-of-death mortality data for the years 1999–2007, a 5-fold increase in mortality attributed to CDI was noted Hall et al. CID 2012;55:216-23
Chart1
1999-2000
2007-2007
4.5
2.8
5
To resize chart data range, drag lower right corner of range.
How did we get here?
• Let’s review a few key concepts on CDI to get everyone up to speed – Pathogenesis – Emergence of ‘hypervirulent’ strains
Copyright ©2004 CMA Media Inc. or its licensors
Poutanen, S. M. et al. CMAJ 2004;171:51-58
Pathogenesis of Clostridium difficile-associated diarrhea in adults
Copyright ©2004 CMA Media Inc. or its licensors Poutanen, S. M. et al. CMAJ 2004;171:51-58
Pathogenesis of Clostridium difficile-associated diarrhea in adults
Hypervirulent C. difficile
Pepin, J. et al. CMAJ 2004;171:466-472
Increasing mortality and complications due to CDAD
Toxins A and toxin B are produced in the Pathogenicity Locus (PaLoc) of C. difficile
McDonald et al. N Eng J Med 2005;353:2433-2441
Codes for toxin B
Codes for toxin A
Negative regulator of tcdA and tcdB
tcdC deficient strain = Lots more production of toxins A and B!
Warny Lancet 2005;366:1079
The C. difficile Epidemic
1. Trends in Microbiology August 2014, Vol. 22, No. 8 2. The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move Valiente, E. et al. Clinical Microbiology and Infection , Volume 20 , Issue 5 , 396 - 404
RT 027 FQR1 in North America and RT 027 FQR2 responsible for worldwide epidemic1
C difficile nomenclature
• All these are synonymous terms: – Toxinotype III: PCR analysis of PaLoc – PCR ribotype 027: European typing method – REA Group BI (bee eye): Typing method by Dale
Gerding (Hines, IL) – PFGE: Nap-1: CDC typing method
• Work currently being conducted to make ribotyping the preferred typing method in the USA and Europe
Who you calling “hypervirulent”
Predictora Derivation OR (95% CI) P Value Validation OR (95% CI) P Value
Hypervirulent ribotype:
027/078 vs non- 027/078 (reference) 0.82 (.07–10.0) .874 1.34 (.53–3.16) .516
White blood cell count: Leukocytosis (>12 000 cells/mL) or leukopenia
(<4000 cells/mL) vs normal (reference) 4.27 (1.14–19.46) .041 2.32 (1.07–5.18) .035
Low albumin level (g/dL) 0.25 (.07–.77) .025 0.47 (.25–.87) .018
Walk et al. CID 2012;doi:10.1093/CID/CIS78
Michigan: Derivation (n=310/34 severe) and validation (n=433/45 severe) of predictors of severe CDI (ICU admission, colectomy, or death). After accounting for disease presentation severity, ribotype did not predict outcome
..and there are more ribotypes than just 027
A lot of ribotypes are associated with CDI
Many ribotypes are virulent, including 027
Ribotype Severe CDI presentation
You are all now expert C diff ribotypers
• 027 is definitely a virulent ribotype • …..but, there are lots of ribotypes that are
equally virulent • Without a doubt, the ribotype 027 strain has
put a large focus on the value of strain typing in C. difficile.
• Now, let’s use this technology to understand where C. diff may be coming from – (answer: everywhere)
Standard view of CDI transmission
PatientSymptomatic Patient with CDI
Asymptomatic Patient with CDI
Healthcare workers Hospital environment
C. difficile is becoming more common in the community setting
0 1 2 3 4 5 6 7 8
No medical conditions
Household member with
P=0.04
P=0.05
Chitnis et al. JAMA Int Med 2013;173:1359-67
• CDC: 10 US states identified 984 patients with community- acquired CDI (No previous antibiotics: 36%; No outpatient healthcare exposure: 18%).
How do patients get infected in the first place? Where are C diff strains coming from?
• Leeds, England: Whole genome sequencing of 1223 cases of CDI. This allows for a highly discriminatory way to see where C diff strains are coming from.
Eyre. N Eng J Med 2013 Sept;369:1195-205
Chart1
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0.53
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0.25
0.52
Percentage of isolates
Animals can be colonized with C. difficile
Sweden1: Ribotype 046 common among neonatal pigs and humans
1. Clin Microbiol Infect 2014;20:02-6 2. J Clin Microbiol 2013;51:3796-3803 3. Frontiers in Microbiology 2014;5:513.
Germany2: RT 078 and 126 were predominant in piglet populations
Japan3: Ribotype 078 isolates genetically related to European PCR RT 078 strains in humans and pigs
New thoughts on CDI transmission 078
Pig in Europe Pig in Japan
Water and soil can also be a reservoir for C. difficile
1. Janezic S, Ocepek M, Zidaric V, Rupnik M. Clostridium difficile genotypes other than ribotype 078 that are prevalent among human, animal and environmental isolates. BMC Microbiology. 2012;12:48. doi:10.1186/1471-2180-12-48.
Slovenia 2008-2010: 786 isolates, 90 isolates of C. difficile isolated
078
014
Prevalence of C. difficile (CD) from various environmental samples. Samples collected from 30
households throughout Houston, TX
Chart1
Shoes
Shoes
Bathroom
Bathroom
Surface
Surface
Dust
Dust
Shoes
63
25
2
Bathroom
15
5
2
Surface
37
7
3
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12
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5
Is C. diff ubiquitous in our environment?
• We hypothesized the community environment may contain a large burden of C. difficile contamination.
• The objectives of the study was to assess community environmental contamination of toxigenic Clostridium difficile – Sub-aims
• compare strain relatedness to clinical strains (ribotype) • assess virulence in a mouse model.
Results, number of samples Isolate source Number
Environmental
61.5
36.9
0 10 20 30 40 50 60 70 80 90
100
Fast-food restaurant (n=125)
**p<0.001 compared to either chain stores or fast-food restaurants
Figure 2. Home environmental contamination of C. difficile
45.3 35.6 38.6
0 10 20 30 40 50 60 70 80 90
100
Shoe sole (n=274) Restroom (n=177) Cleaning supply (n=171)
Kitchen (n=334)
Table 1. Risk factors for home contamination with C. difficile
C diff positive C diff negative P value Home type House 41 (36%) 71 >0.3 Apartment 162 (43%) 215 Pet in home Yes 41 (65%) 22 <0.001 No 144 (38%) 233 Number of persons in home 3.6±1.9 3.2±1.3 >0.3 Age of oldest person in home 42±16 44±16 >0.3 Age of youngest in home 20±7 21±11 >0.3 Any child in daycare 10 (5%) 11 (4%) >0.3
Ribotype distribution of clinical vs. environmental C difficile isolates
0%
5%
10%
15%
20%
25%
30%
Environmental (n=401) Clinical (n=613)
Most of the other environmental samples have been conducted in Europe.
How do our results compare to Europe?
Houston, TX
Paris, France Berlin, Germany
Lucky for me, I had a student do an internship in Paris and Berlin last Summer!
Area swabbed No C. difficile found C. difficile isolated
Berlin (n=100) Paris (n=100) Overall Prevalence 22/100 (22%) 20/100 (20%)
Surface swabbed Floor 19/85 (22%) 14/37 (38%)
Bench 3/15 (20%) 4/53 (8%) Other** 2/10 (20%)
Location Parks 6/11 (55%) 4/42 (10%)
Metro/bus 14/75 (19%) 9/18 (50%) Public areas*** 2/14 (14%) 7/40 (18%)
Ribotype 078-126 0/22 (0%) 0/20 (0%) 014-020 10/22 (46%) 1/20 (5%)
27 0/22 (0%) 1/20(5%) 2 1/22 (5%) 1/20(5%)
UM9 0/22 (0%) 2/20 (10%) UM10 1/22 (5%) 1/20 (5%) UM11 0/22 (0%) 5/20 (25%) UM12 4/22 (18%) 3/20 (15%) UM13 3/22 (14%) 2/20 (10%) UM16 0/22 (0%) 2/20 (10%) UM18 3/22 (14%) 0/20 (0%) UM26 0/22 (0%) 2/26 (8%)
**Other defined as bike handle station release button, board, and side rails, ***excluding parks and metro/bus areas
Environmental C. difficile in Berlin and Paris
Environmental C. difficile Prevalence in Berlin and Paris
32.0%
54.5%
9.5%
34.4%
18.7%
50.0%
0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00%
100.00%
Parks Metro/bus Public areas***
**defined as bike handle station release button, board, and side rails
Texas vs. Europe C. difficile environmental prevalence
Community environmental studies on potentially pathogenic Clostridium difficile
Overall: 219/1040 (21%)
Parks: 97/235 (41%)
Houses: 61/175 (35%)
An Epidemiological Survey of Environmental Clostridium difficile in Berlin and Paris
Overall*: 21%
Parks: 32%
Houses: n/a
Host factors that increase vulnerability to CDI might be of more importance than increased exposure to C. difficile
Patient at risk for CDI
Now that I’ve totally rocked your C. diff infection control world!!
• How should we treat this ubiquitous pathogen? • Current practice
– Metronidazole (40-60% of total use) – Oral vancomycin (20-40% of total use) – Fidaxomicin (<10% of total use)
• Is this the correct use of these drugs?
Treatment of Clostridium difficile infection. Kill the bug and treat the patient
Adamu and Lawley. Curr Opin Microbiol 2013 40
Expanding treatment goals for CDI
Adamu and Lawley. Curr Opin Microbiol 2013 41
Essential: Correct dysbiosis Kill the organism Adaptive immunity
Optional Safe and convenient Also affects toxins Short vs. long-term but nice: and spores
A A
There has been an explosion in treatment possibilities for CDI
Current: Probiotics Metronidazole IVIG FMT Vancomycin
Fidaxomicin
Future: 2nd generation FMT Surotomycin Monocloncal antibodies non-tox C diff M3 Cadazolid vs. C diff toxins Ecobiotics SMT-19969 Toxoid vaccines
A A
B
Current US IDSA CDI guidelines 2010 Episode Clinical Signs Severity Recommended
agent Dosing Regimen Strength of
Recommendation
Mild or moderate
A-I
Initial WBC ≥ 15, 000 or SrCr ≥ 1.5 X premorbid level
Severe Vancomycin 125 mg PO four times daily 10-14 days
B-I
Severe, complicated
Vancomycin + metronidazole IV
Vancomycin: 500 mg PO or NG four times daily + Metronidazole: 500 mg IV q8hours. For ileus, consider adding rectal instillation of vancomycin
C-III
Third (2nd
B-III
Cohen SH, Gerding DN, et al. Infection control and hospital epidemiology. 2010 (May); 31(5) 43
Current European CDI guidelines
Vancomycin Fidaxomicin
Green: strongly supports use; Blue: moderately supports use; Grey: Minimally supports use; Red: recommend to not use
44Clin Microbiol Infect 2014
More recently, metronidazole has been shown to be globally inferior to vancomcyin (tolevamer phase III RCT)
Johnson S et al. Clin Infect Dis. 2014;59:345-354 45
Chart1
4.5
2.8
5
Why are patients failing metronidazole?
Age
<50 (n=72) 50-70 (n=97) >70 (n=73) P
value Continued use of antibiotics 38 (53%) 61 (63%) 45 (62%) 0.38 CDI severity 21 (29%) 59 (61%) 48 (66%) <0.01 Horn's index > 2 14 (19%) 29 (30%) 28 (38%) 0.043
Pham,…, Garey. AAC 2015 46
Summary of metro vs. vanco clinical studies
47
Clinical failure Recurrence
Study Year Location n Single center Blinded Randomized Metro dose Vanco dose metro vanco metro vanco
Teasley, 1983 82-83 MN 101 yes no yes 250 mg QID 500 mg qid 2 of 37
(5.4%) 0 of 45
6 of 45 (13%)
Wenisch, 1996 93-95 Austria 62 yes no yes 500 mg TID 500 mg tid 2 of 31
(6%) 2 of 31
5 of 31 (16%)
Musher, 2006 02-04 USA
(Houston) 34 no yes yes 250 mg QID 125 mg qid 6 of 34 (17%) N/A 9 of 28
(32%) N/A
Zar, 2007 94-02 Chicago 150 Yes yes yes 250 mg QID 125 mg qid 13 of 79 (16%)
2 of 71 (3%)
9 of 66 (14%)
5 of 69 (7%)
Johnson, 2013 05-07 World 552 no yes yes 375 mg QID 125 mg qid 76 of 278
(27%) 49 of 259
(19%) 48 of 202
(23%) 43 of 210
(21%)
There may have been a MIC creep with metronidazole over the decades
48
Metronidazole Author Location Time period Isolates MIC50 MIC90 Range All strains Hecht et al Various 1983–2004 110 0.125 0.25 0.025–0.5 Edlund et al Sweden 1998 50 0.125 0.25 0.125–0.25 Betriu et al Spain 2001 55 0.5 1 ≤0.06–1 Citron et al USA 2003 18 0.5 1 0.25–1 Finegold et al USA (CA) 2003 72 0.5 1 0.25–2 Karlowsky et al Canada
(Manitoba) 2007 208 0.5 1 0.25–4
Debast et al Europe 2008 398 0.25 0.5 <0.06-2 Reigadas et al Spain 2013 100 0.25 0.5 0.06-1 Snydman et al USA 2011-12 925 1 2 <0.06-4 BI/027/Nap1 strains Citron et al USA 2004–2005 NR 2 0.5–2 Debast et al Europe 2008 0.5 1 0.5-1 Snydman et al USA 2011-12 2 2 <0.06-4
Shah et al. Expert Rev Anti Infect Ther 2011
There is a possibility that higher MICs of metronidazole may have often gone unnoticed
• MIC increased 2-4 fold after exposure to 1-2 passages of sub-MIC metronidazole (Moura, JAC 2013)
• The addition of hemin to media decreased metronidazole susceptibility of C. difficile (Wu, ICAAC 2015)
• We don’t test for MIC susceptibility very often
49
• Mean concentrations of metronidazole in stool: <0.25-9.5 ug/g
• MIC50: 1 ug/ml MIC90: 2 ug/ml – May be higher
• A poor response rate to metronidazole should be expected given these numbers!
50Bolton et al. Gut 1986
Explosion in treatment possibilities for CDI minus 1
Fidaxomicin
A A
B
Fidaxomicin: Equal efficacy at vancomycin to cure patients and lessens the risk of recurrence
Louie et al. N Eng J Med 2011;364:422-310
The second phase III study showed similar results (Crook et al. Lancet ID)
52
Chart1
4.5
2.8
5
Recurrence rates of CDI in patients given fidaxomicin vs. vancomycin in the phase III study. Results from the per protocol analysis shown below.
Louie et al. N Eng J Med 2011 Cornely et al. Lancet ID 2012
The second phase III study showed similar results Recurrence with 027: Fidaxo: 22% Vanco: 38%
“Hypervirulent” 027 strain Other strains
Chart1
BI/Nap1/027
BI/Nap1/027
4.5
2.8
5
However, this drug is quite costly: Fidaxomicin Use By Region
54
Northeast 2011 – 0%
Appropriate use of fidaxomicin
• Because of high acquisition cost, fidaxomicin has been reserved for a very select patient population (my best guess)
• Remember: fidaxomicin’s primary MOA is its narrow spectrum of activity preserving host microbiota
• Has reserving fidaxomicin for the worst cases been a good idea?
• Answer: No
55
We really have to do a better job of using fidaxomicin correctly
56
Episode ≥ 3 (n=33)
Mild-Moderate CDI; n(%) 10 (27%) 12 (37.5%) 22 (32%) N/A 22/69 (32%) Severe CDI; n(%) 27 (73%) 20 (62.5%) 47 (68%) N/A 47/69 (68%) 1. FDX monotherapy; n (%) 3 (8% ) 4 (12.5%)* 7 (12%) 6 (18%) 13 (13%) 2. Other CDI therapy; n (%) 34 (92%) 27 (84%) 61 (88%) 27 (82%) 88 (86%) I. Subsequent; n 18 14 32 16 48 II. Subsequent and combination; n
8 6 14 2 16
III. Combination; n 2 1 3 1 4 IV. Unable to categorize; n 6 6 12 8 20 Concomitant non-CDI antibiotics; n (%)
25 (68%) 10 (31%) 35 (51%) 13 (39%) 48 (47%)
Multicenter, 11 hospital chart review study of hospitalized patients with CDI that received fidaxomicin between 2011 and 2013.
Shah, ICAAC 2015
How do we decide who to give fidaxomicin to?
• As far as I can tell, 100% of the money we have used on fidaxomicin has been a waste of money (only kind of kidding).
• Can the anti-recurrence effect of fidaxomicin offset its high acquisition cost?
57
* Of disease-attributable readmission, 85% returned to the initial hospital for care
Aitken, DuPont, Garey. PLOS One 2014 July 24;9(7) 58
Chart1
Percentage of total
Outpatient only
Cost in US dollars;
Total hospitalization^ $20, 693 (11, 287 - 41, 386)
$45, 148 (20, 693 - 82,772)
Shah et al. ICAAC 2014 Poster #K-356, Sat, Sept 6, 2014 59
Chart1
Sheet3
*Age (Mean ± SD): 62±17 years ; Gender: Female - 58%; Male - 42%; Horn’s index (scoring of underlying illness): Score of 3 (Severe) : 46%; Score of 4 (extremely severe): 7% **Primary CDI: labeled as without recurrent CDI ^Primary + recurrent CDI: labeled as with recurrent CDI
Sheet1
60
Patients who received oral vancomycin (n=46) or fidaxomicin (n=49) for the treatment of CDI via a protocol that encouraged fidaxomicin for select patients.
CDI-related re-admissions: Fidaxo: 20.4%; Vanco: 41.3%
Drug acquisition costs Hospital re-admission costs
Gallagher et al. AAC 2015
Chart1
Vancomycin
Fidaxomicin
196,200
2.8
5
Real-world evidence that fidaxomicin may reduce these costs?
10.6
16.3
21.1
7.7
12.9
16.9
5.4
12.5
8.3
11.8
9
5.8
0
5
10
15
20
25
A (n=98) B (n=162) D (n=127) C (n=511) E (n=209) F (n=178) G (n=278)
90 -d
ay h
os pi
Goldenberg, Eur J Clin Microbiol Infect Dis 2016
0
5
10
15
20
25
30
35
A (n=98) B (n=162) D (n=127) C (n=511) E (n=209) F (n=178) G (n=278)
Re -a
dm is
si on
w ith
in 3
0 da
ys o
UK, 2012-13 : seven hospitals incorporate fidaxomicin into clinical protocols. Letters below indicate individual hospitals. Mortality rates decreased from 18.2% and 17.3% to 3.1% and 3.1% in hospitals A and B, respectively (p<0.05, each)
P<0.05
Goldenberg, Eur J Clin Microbiol Infect Dis 2016
I do also wonder if we are missing the most important endpoints?
Aitken et al. ICAAC 2014 Poster #K-360, Sat, Sept 6, 2014
Chart1
SF36 score (average)
Overall SF36
4.5
2.8
5
The driver for decreased QOL is not so much physical as a worry/anxiety of transmissibility or persistence of
symptoms
Final thoughts on antibiotic treatment
• Limit use of metronidazole as alternative agent • Consider a certain budget that you can afford to
prove the worth of fidaxomicin and then use it for that purpose (first recurrence?).
• As more narrow-spectrum branded drugs become available, may have to prove themselves in other pharmacologic niches (decreased toxin expression). – This assumes similar phase III results
65
Fidaxomicin
A A
B
Serum concentrations of IgG antibodies against toxin A, toxin B, and non-toxin antigens
Kyne et al. Lancet 2001;357:189-93
Single episode Recurrent diarrhea Single episode
Phase III studies of actoxumab (acto) and bezlotoxumab (bezlo): Overall
68Modify I Modify IIWilcox et al. ICAAC 2015 Gerding et al. ICAAC 2015
Chart1
69Modify I Modify II
33%
2.8
5
Conclusion
• As long as we live in a world of elderly, hospitalized patients given broad spectrum antibiotics, CDI is here to stay
• With a coordinated effort and contemporary epidemiologic techniques, we can likely control and respond to future changes in the pathogenesis of CDI
• With a little luck and good science, we may also be able to discover new insights into strategies to prevent and control CDI.
An Update on Clostridium difficile Infection: From Infection Control to Treatment
71 Source: CDC Report "Antibiotic Resistance Threats in the United States, 2013” Lessa CF et al. NEJM 2015;372:825-34.
500,000 29,000
New 2011 Data
Lessa et al, N Eng J Med 2015: 34.2% of CDI cases were considered community-acquired
Kevin W. Garey, PharmD, MS. Professor and Chair University of Houston College of Pharmacy
An Update on Clostridium difficile Infection: From Infection Control to Treatment
Objectives
A History of C. difficile
C. difficile is the main contributor to gastroenteritis-associated deaths in the USA
How did we get here?
Slide Number 6
Slide Number 7
Hypervirulent C. difficile
Slide Number 10
Toxins A and toxin B are produced in the Pathogenicity Locus (PaLoc) of C. difficile
Time course of toxin production by hypervirulent strain compared to control
The C. difficile Epidemic
Slide Number 18
C. difficile is becoming more common in the community setting
How do patients get infected in the first place? Where are C diff strains coming from?
Slide Number 21
Slide Number 23
Water and soil can also be a reservoir for C. difficile
Slide Number 25
Prevalence of C. difficile (CD) from various environmental samples. Samples collected from 30 households throughout Houston, TX
Is C. diff ubiquitous in our environment?
Results, number of samples
Table 1. Risk factors for home contamination with C. difficile
Ribotype distribution of clinical vs. environmental C difficile isolates
Most of the other environmental samples have been conducted in Europe. How do our results compare to Europe?
Lucky for me, I had a student do an internship in Paris and Berlin last Summer!
Environmental C. difficile in Berlin and Paris
Environmental C. difficile Prevalence in Berlin and Paris
Texas vs. EuropeC. difficile environmental prevalence
Slide Number 38
Now that I’ve totally rocked your C. diff infection control world!!
Treatment of Clostridium difficile infection. Kill the bug and treat the patient
Expanding treatment goals for CDI
There has been an explosion in treatment possibilities for CDI
Current US IDSA CDI guidelines 2010
Current European CDI guidelines
More recently, metronidazole has been shown to be globally inferior to vancomcyin (tolevamer phase III RCT)
Why are patients failing metronidazole?
Summary of metro vs. vanco clinical studies
There may have been a MIC creep with metronidazole over the decades
There is a possibility that higher MICs of metronidazole may have often gone unnoticed
Bottom line: this may simply be a PK/PD problem
Explosion in treatment possibilities for CDI minus 1
Fidaxomicin: Equal efficacy at vancomycin to cure patients and lessens the risk of recurrence
Recurrence rates of CDI in patients given fidaxomicin vs. vancomycin in the phase III study. Results from the per protocol analysis shown below.
However, this drug is quite costly:Fidaxomicin Use By Region
Appropriate use of fidaxomicin
We really have to do a better job of using fidaxomicin correctly
How do we decide who to give fidaxomicin to?
Recurrent CDI is costly:Healthcare utilization for recurrent CDI
Increased healthcare utilization = increased healthcare costs
Any evidence that fidaxomicin may reduce these costs?
I do also wonder if we are missing the most important endpoints?
The driver for decreased QOL is not so much physical as a worry/anxiety of transmissibility or persistence of symptoms
Final thoughts on antibiotic treatment
Explosion in treatment possibilities for CDI: Augment immune response!
Serum concentrations of IgG antibodies against toxin A, toxin B, and non-toxin antigens
Phase III studies of actoxumab (acto) and bezlotoxumab (bezlo): Overall
Phase III studies of actoxumab (acto) and bezlotoxumab (bezlo):027/Nap1/BI strain
Conclusion

Documents

An Update on Clostridium difficile Infection: From